Applications of Modern Electroanalytical Techniques to Pharmaceutical Chemistry

Abstract

0 The apparent partition coefficients between n-octyl alcohol and aqueous buffers (ranging from pH 2.1 to 8.5) were determined for several tetracyclines. Using the previously suggested microscopic dissociation constants for tetracycline, the relative amounts of each microscopic ionic form of tetracycline theoret- ically present at each pH were calculated. The zwitterionic form, O+ (tricarbonyl methane system ionized, phenolic diketone moiety unionized, dimethylammonium cation postively charged), which was present in highest concentration in the pH range from 4 to 7, appeared to be the most lipid soluble form, its reduced polarity possibly resulting from an intramolecular type of ion-pair formation. Possible relationships between the biological activity of the various tetracycline analogs and their pH-octanol solubility profiles have been discussed. Keyphrases 0 Tetracyclines-pH-partition behavior 0 Apparent partition coefficients-tetracyclines between n-octanol, aqueous buffers 0 Biological activity relationship, tetracyclines-pH-octanol solubility profiles 0 UV spectrophotometry-analysis The work of Pindell et al. (1) has demonstrated that tetracycline is fairly rapidly absorbed from the duo- denum of the dog and that some absorption can also occur from the stomach when gastric emptying is de- layed. However, only a surprisingly small amount (3.1 %) of the total administered dose was actually absorbed in 1.5 hr. The amounts of tetracycline absorbed were directly proportional to the dose over a tenfold range. These factors have suggested that tetracycline absorption is a passive diffusion phenomenon. Structural modifications have been shown to alter the gastrointestinal absorption of the tetracyclines. For example, one recent study showed that the extent of minocycline absorption from the gastrointestinal tract of dogs was two to three times greater than with tetracycline (2). Doxycycline has been shown to produce nearly identical initial plasma levels as demethylchlortetracycline upon oral administration to fasting hu- mans, even though the dose of the latter was three times as great (3). Structural modifications can likewise in- fluence the renal clearance of tetracyclines. Although they are bound to protein to nearly the same extent, doxycycline has been shown to have a 12 of creatinine clearance in man while demethylchlortetracycline was shown to have a 27 of creatinine clearance in the same study (3). The general structural formula for the tetra- cycline analogs is shown as Fig. 1, and the structures of the analogs discussed in this paper are listed in Table I and explained in terms of the general structure in Fig. 1. The tetracyclines are ionized throughout the physio- logical pH range, existing in cationic form at more acidic pH values, in anionic form at more alkaline pH values, 1184 0 Journal of Pharmaceutical Sciences